CN108219030A - A kind of preparation method of Enoxaparin Sodium crude product - Google Patents
A kind of preparation method of Enoxaparin Sodium crude product Download PDFInfo
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- CN108219030A CN108219030A CN201611191786.5A CN201611191786A CN108219030A CN 108219030 A CN108219030 A CN 108219030A CN 201611191786 A CN201611191786 A CN 201611191786A CN 108219030 A CN108219030 A CN 108219030A
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- 229960005153 enoxaparin sodium Drugs 0.000 title claims abstract description 39
- CIJQTPFWFXOSEO-NDMITSJXSA-J tetrasodium;(2r,3r,4s)-2-[(2r,3s,4r,5r,6s)-5-acetamido-6-[(1r,2r,3r,4r)-4-[(2r,3s,4r,5r,6r)-5-acetamido-6-[(4r,5r,6r)-2-carboxylato-4,5-dihydroxy-6-[[(1r,3r,4r,5r)-3-hydroxy-4-(sulfonatoamino)-6,8-dioxabicyclo[3.2.1]octan-2-yl]oxy]oxan-3-yl]oxy-2-(hydroxy Chemical compound [Na+].[Na+].[Na+].[Na+].O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1O)NC(C)=O)O[C@@H]1C(C[C@H]([C@@H]([C@H]1O)O)O[C@@H]1[C@@H](CO)O[C@H](OC2C(O[C@@H](OC3[C@@H]([C@@H](NS([O-])(=O)=O)[C@@H]4OC[C@H]3O4)O)[C@H](O)[C@H]2O)C([O-])=O)[C@H](NC(C)=O)[C@H]1C)C([O-])=O)[C@@H]1OC(C([O-])=O)=C[C@H](O)[C@H]1O CIJQTPFWFXOSEO-NDMITSJXSA-J 0.000 title claims abstract description 39
- 239000012043 crude product Substances 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 229920000669 heparin Polymers 0.000 claims abstract description 57
- 229960002897 heparin Drugs 0.000 claims abstract description 39
- -1 heparin benzyl ester salt Chemical class 0.000 claims abstract description 38
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 claims abstract description 17
- 229960001008 heparin sodium Drugs 0.000 claims abstract description 16
- 239000007788 liquid Substances 0.000 claims description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 33
- 239000000243 solution Substances 0.000 claims description 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 239000008213 purified water Substances 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 16
- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 claims description 15
- 229960001950 benzethonium chloride Drugs 0.000 claims description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 14
- 239000012065 filter cake Substances 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 238000009938 salting Methods 0.000 claims description 8
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 claims description 7
- 229940073608 benzyl chloride Drugs 0.000 claims description 7
- 239000011780 sodium chloride Substances 0.000 claims description 7
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 5
- 238000004062 sedimentation Methods 0.000 claims description 5
- 239000001632 sodium acetate Substances 0.000 claims description 5
- 235000017281 sodium acetate Nutrition 0.000 claims description 5
- YRTWNFXASSUQEW-UHFFFAOYSA-M sodium;methanol;acetate Chemical compound [Na+].OC.CC([O-])=O YRTWNFXASSUQEW-UHFFFAOYSA-M 0.000 claims description 5
- 238000001291 vacuum drying Methods 0.000 claims description 3
- 238000000967 suction filtration Methods 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims 1
- 239000000047 product Substances 0.000 abstract description 27
- 230000000694 effects Effects 0.000 abstract description 7
- 230000015556 catabolic process Effects 0.000 abstract description 4
- 238000006731 degradation reaction Methods 0.000 abstract description 4
- 230000032050 esterification Effects 0.000 abstract description 2
- 238000005886 esterification reaction Methods 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 238000000034 method Methods 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract 1
- 150000003839 salts Chemical class 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 23
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 10
- 239000003814 drug Substances 0.000 description 10
- 239000011734 sodium Substances 0.000 description 10
- 229910052708 sodium Inorganic materials 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 230000008859 change Effects 0.000 description 7
- 235000011121 sodium hydroxide Nutrition 0.000 description 6
- 238000012360 testing method Methods 0.000 description 5
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 4
- 230000007774 longterm Effects 0.000 description 4
- 238000005374 membrane filtration Methods 0.000 description 4
- 150000002978 peroxides Chemical class 0.000 description 4
- 230000003252 repetitive effect Effects 0.000 description 4
- 239000013049 sediment Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 150000004679 hydroxides Chemical class 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 229960000610 enoxaparin Drugs 0.000 description 2
- 108010079356 FIIa Proteins 0.000 description 1
- 108010074860 Factor Xa Proteins 0.000 description 1
- 241000165940 Houjia Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 229940095054 ammoniac Drugs 0.000 description 1
- 230000001858 anti-Xa Effects 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 238000007068 beta-elimination reaction Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000000415 inactivating effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 210000004347 intestinal mucosa Anatomy 0.000 description 1
- 239000003055 low molecular weight heparin Substances 0.000 description 1
- 229940127215 low-molecular weight heparin Drugs 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0075—Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0075—Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
- C08B37/0078—Degradation products
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- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
Abstract
The invention discloses a kind of preparation method of Enoxaparin Sodium crude product, using heparin sodium as raw material, through into salt, esterification, depolymerization and etc. obtain Enoxaparin Sodium crude product.Method disclosed by the invention can effectively solve the problem that dissolvent residual is big, decolorizing effect is undesirable and the non-uniform problem of heparin benzyl ester salt degradation, reduces production cost, increases product stability, improves product quality.
Description
Technical field
The present invention relates to pharmaceutical synthesis field, more particularly to a kind of preparation method of Enoxaparin Sodium crude product.
Background technology
Enoxaparin Sodium is researched and developed for the first time by the fourth-largest drugmaker's Sanofi-Aventis (Sanofi-Aventis) in the world,
U.S. FDA approval listing is obtained on March 29th, 1993, becomes the best-selling drug of Sanofi-Aventis company.Enoxaparin Sodium
For one kind of low molecular sodium heparin, be the heparin extracted by pig intestinal mucosa after benzyl is esterified, sulfate of ammoniac that alkaline degradation obtains
The sodium salt of base dextran fragments, for polysaccharide mixture, weight average molecular weight 4500D.Its main mechanism be by with anti-freezing
Hemase III and its compound combine, and inhibit the activity of factor Xa, II a, Ⅸ a, Ⅺ a, Ⅻ a, wherein mainly by inhibiting Xa
Play anticoagulation.The anti-Xa of low molecular weight heparin, II a activity are mainly related to molecular chain length, and the strand of Enoxaparin is big
Be less than 18 sugared units more, the effect for inactivating Xa it is stronger and to the effect smaller of II a.The anti-II a ratios of Xa/ of Enoxaparin are 4：1,
It is significantly higher than unfractionated heparin 1：1, therefore with stronger anti thrombotic action.
The preparation method of existing Enoxaparin Sodium, mainly CN100582123C, CN102050888B and
Technique disclosed in CN102585037A is using heparin sodium as starting material, by β-elimination in salinization, esterification, lye
Product is obtained, but there are carboxylate degradation is uneven, product colour is deep, clarity is poor, yield is low, quality is unstable for prior art
The problems such as.
Invention content
The purpose of the present invention is to provide a kind of preparation methods of Enoxaparin Sodium crude product, can effectively overcome at present according to promise liver
The problems in plain sodium preparation process improves product potency and yield, reduces production cost, improves product quality.
In order to achieve the object of the present invention, inventor finally obtains technical solution of the present invention, the technology by a large number of experiments
Scheme includes the following steps：
1) benzethonium chloride aqueous solution is slowly added in heparin sodium water solution, it will after reaction being stirred at room temperature 2-4 hours
Reaction solution filters, purifying water washing, is dried in vacuo to obtain heparin quaternary ammonium salt；
2) heparin quaternary ammonium salt obtained by step 1) is dissolved in dichloromethane, adds in benzyl chloride, react 21- at 30-40 DEG C
Room temperature is down to after 25 hours, adds in 10% sodium acetate methanol solution, standing sedimentation 3 hours after being stirred to react 20-40 minutes is taken out
Filter, gained filter cake are dried in vacuo to obtain heparin benzyl ester salt at room temperature；
3) heparin benzyl ester salt obtained by step 2) is dissolved in water and is made into heparin benzyl ester salting liquid, be heated to 60-65 DEG C, Ran Houjia
Enter the sodium hydroxide solution with the 0.2M of isometric 60-65 DEG C of heparin benzyl ester salting liquid, 0-5 is cooled to after being stirred to react 1 hour
DEG C, it is 6.5-6.8 that reaction solution PH is adjusted after suction filtration, and sodium chloride is added to be made into salting liquid, is taken out after being settled 3 hours with 2.5-4 times of methanol
Filter, filter cake are dried in vacuo to obtain Enoxaparin Sodium crude product at 40 DEG C.
4) Enoxaparin Sodium crude product is added in purified water, stirring and dissolving forms the medicine of 25% concentration (mass percent)
Liquid after adjusting pH to 9.5 with the sodium hydrate aqueous solution of 1mol/L, adds in a concentration of 30% peroxide of 1.0% medicine liquid volume
Change hydrogen, after persistently stirring 20 hours, pH to 7.0 adjusted with the aqueous hydrochloric acid solution of 1mol/L, backward liquid in be gradually added 3.0
The sodium chloride of (mass ratio) is measured again, is stirred to the methanol (mass volume ratio) for being completely dissolved 20 times of amounts of addition in backward liquid, it is heavy
It forms sediment, filters to obtain Enoxaparin Sodium centre product；Enoxaparin Sodium finished product is obtained by this step repetitive operation is primary.
5) Enoxaparin Sodium finished product is added in purified water, stirring and dissolving forms the medicine of 45% concentration (mass percent)
Liquid, liquid is through 0.1 μm of membrane filtration, spray drying.
Wherein, heparin sodium water solution is dissolved in the heparin sodium of 1 parts by weight in the purified water of 12-14 parts by weight in step 1)
And obtain, benzethonium chloride aqueous solution be the benzethonium chloride of 2.2-2.8 parts by weight is dissolved in the purified water of 4.5-5.5 parts by weight and
, vacuum drying temperature is 45-55 DEG C.
It is that the heparin quaternary ammonium salt of 1 parts by weight is dissolved in the dichloromethane of 9-13 times of parts by volume in step 2), benzyl chloride
Dosage is 2 times of heparin quaternary ammonium salt quality, and the dosage of sodium acetate is 2 times of heparin quaternary ammonium salt quality.
Heparin benzyl ester salting liquid is that the heparin benzyl ester salt of 1 parts by weight is dissolved in the water of 10-14 parts by weight in step 3), chlorine
Change 1.5-3.0 times that sodium dosage is heparin benzyl ester salt.
Compared with prior art, technical scheme of the present invention has the advantages that：
A, dissolvent residual is extremely low；
B, good decolorizing effect (after 12 months long term tests, product solution is still clarified, and color is shallower than yellow 1),
Impurity is few, and product stability is high；
C, potency is high, and potency ratio, suitable for (FXa/FIIa is between 3.8-4.5), product anti-thrombus activity is high, reduces life
Finished product improves product quality.
D, the degradation of heparin benzyl ester salt is uniform, and molecular weight ranges are preferably.
Specific embodiment
The following is specific embodiments of the present invention, and technical scheme of the present invention is further described, but of the invention
Protection domain be not limited to these embodiments.It is every to be included in this hair without departing substantially from the change of present inventive concept or equivalent substitute
Within bright protection domain.Product testing of the present invention is performed by European Pharmacopoeia relevant criterion.
Embodiment 1
The benzethonium chloride of 2.5 parts by weight is dissolved in the purified water of 5 parts by weight and is made into benzethonium chloride solution；By 1 parts by weight
Heparin sodium be dissolved in the purified water of 13 parts by weight and be made into heparin sodium aqua, benzethonium chloride solution is slowly added to liver under stirring
In plain sodium solution, temperature is room temperature.After adding, it is stirred to react 3h at room temperature, filters, filter cake is drained after being washed with water 3 times, 50 DEG C
Lower vacuum drying obtains heparin quaternary ammonium salt solid.
The heparin quaternary ammonium salt of 1 parts by weight is dissolved in the dichloromethane of 11 times of parts by volume, adds in the benzyl chloride of 2 parts by weight,
25h is reacted at 40 DEG C, is cooled to room temperature, the 10% sodium acetate methanol solution that the sodium acetate of 2 parts by weight is made into is added with stirring, stirs
It mixes after forty minutes, standing sedimentation 3h, filters, filter cake is dried in vacuo at room temperature, obtains heparin benzyl ester salt.
The heparin benzyl ester salt of 1 parts by weight is dissolved in 14 times of water, is had warmed up with isometric to 65 DEG C of 0.2M hydroxides
Sodium after temperature control stirring reaction 1h, is cooled to 0 DEG C, filtering, it is 6.7 to adjust filtrate PH, adds the chlorination of 2 parts by weight at 65 DEG C
Sodium after being completely dissolved, adds in 4 times of volumes methanols, settles 3h, filters, and filter cake is dried in vacuo at 40 DEG C, obtains Enoxaparin Sodium
Crude product.
Enoxaparin Sodium crude product is added in purified water, stirring and dissolving forms the medicine of 25% concentration (mass percent)
Liquid after adjusting pH to 9.5 with the sodium hydrate aqueous solution of 1mol/L, adds in a concentration of 30% peroxide of 1.0% medicine liquid volume
Change hydrogen, after persistently stirring 20 hours, pH to 7.0 adjusted with the aqueous hydrochloric acid solution of 1mol/L, backward liquid in be gradually added 3.0
The sodium chloride of (mass ratio) is measured again, is stirred to the methanol (mass volume ratio) for being completely dissolved 20 times of amounts of addition in backward liquid, it is heavy
It forms sediment, filters to obtain Enoxaparin Sodium centre product；Enoxaparin Sodium finished product is obtained by this step repetitive operation is primary.By Enoxaparin Sodium into
Product are added in purified water, and stirring and dissolving forms the liquid of 45% concentration (mass percent), liquid through 0.1 μm of membrane filtration,
It is spray-dried to obtain Enoxaparin Sodium highly finished product.
Gained Enoxaparin Sodium is detected after the long term test of 12 months, as a result as follows：
Embodiment 2
The benzethonium chloride of 2.2 parts by weight is dissolved in the purified water of 4.5 parts by weight and is made into benzethonium chloride solution；By 1 weight
The heparin sodium of part, which is dissolved in the purified water of 12 parts by weight, is made into heparin sodium aqua, is slowly added to benzethonium chloride solution under stirring
In heparin sodium aqua, temperature is room temperature.After adding, it is stirred to react 2h at room temperature, filters, filter cake is drained after being washed with water 3 times, and 45
It is dried in vacuo at DEG C, obtains heparin quaternary ammonium salt solid.
The heparin quaternary ammonium salt of 1 parts by weight is dissolved in the dichloromethane of 9 times of parts by volume, the benzyl chloride of 2 parts by weight is added in, 30
21h is reacted at DEG C, is cooled to room temperature, is added with stirring the 10% sodium acetate methanol solution that the sodium acetate of 2 parts by weight is made into, is stirred
After twenty minutes, standing sedimentation 3h is filtered, and filter cake is dried in vacuo at room temperature, obtains heparin benzyl ester salt.
The heparin benzyl ester salt of 1 parts by weight is dissolved in 10 times of water, is had warmed up with isometric to 65 DEG C of 0.2M hydroxides
Sodium after temperature control stirring reaction 1h, is cooled to 5 DEG C at 60 DEG C, and filtering, it is 6.8 to adjust filtrate PH, adds the chlorine of 1.5 parts by weight
Change sodium, after being completely dissolved, add in 2.5 times of volumes methanols, settle 3h, filter, filter cake is dried in vacuo at 40 DEG C, obtains according to promise liver
Plain sodium crude product.
Enoxaparin Sodium crude product is added in purified water, stirring and dissolving forms the medicine of 25% concentration (mass percent)
Liquid after adjusting pH to 9.5 with the sodium hydrate aqueous solution of 1mol/L, adds in a concentration of 30% peroxide of 1.0% medicine liquid volume
Change hydrogen, after persistently stirring 20 hours, pH to 7.0 adjusted with the aqueous hydrochloric acid solution of 1mol/L, backward liquid in be gradually added 3.0
The sodium chloride of (mass ratio) is measured again, is stirred to the methanol (mass volume ratio) for being completely dissolved 20 times of amounts of addition in backward liquid, it is heavy
It forms sediment, filters to obtain Enoxaparin Sodium centre product；Enoxaparin Sodium finished product is obtained by this step repetitive operation is primary.By Enoxaparin Sodium into
Product are added in purified water, and stirring and dissolving forms the liquid of 45% concentration (mass percent), liquid through 0.1 μm of membrane filtration,
It is spray-dried to obtain Enoxaparin Sodium highly finished product.
Gained Enoxaparin Sodium is detected after the long term test of 12 months, as a result as follows：
Embodiment 3
The benzethonium chloride of 2.8 parts by weight is dissolved in the purified water of 5.5 parts by weight and is made into benzethonium chloride solution；By 1 weight
The heparin sodium of part, which is dissolved in the purified water of 14 parts by weight, is made into heparin sodium aqua, is slowly added to benzethonium chloride solution under stirring
In heparin sodium aqua, temperature is room temperature.After adding, it is stirred to react 4h at room temperature, filters, filter cake is drained after being washed with water 3 times, and 55
It is dried in vacuo at DEG C, obtains heparin quaternary ammonium salt solid.
The heparin quaternary ammonium salt of 1 parts by weight is dissolved in the dichloromethane of 13 times of parts by volume, adds in the benzyl chloride of 2 parts by weight,
23h is reacted at 35 DEG C, is cooled to room temperature, the 10% sodium acetate methanol solution that the sodium acetate of 2 parts by weight is made into is added with stirring, stirs
After mixing 30 minutes, standing sedimentation 3h is filtered, and filter cake is dried in vacuo at room temperature, obtains heparin benzyl ester salt.
The heparin benzyl ester salt of 1 parts by weight is dissolved in 12 times of water, is had warmed up with isometric to 65 DEG C of 0.2M hydroxides
Sodium after temperature control stirring reaction 1h, is cooled to 3 DEG C, filtering, it is 6.5 to adjust filtrate PH, adds the chlorination of 3 parts by weight at 63 DEG C
Sodium after being completely dissolved, adds in 3 times of volumes methanols, settles 3h, filters, and filter cake is dried in vacuo at 40 DEG C, obtains Enoxaparin Sodium
Crude product.
Enoxaparin Sodium crude product is added in purified water, stirring and dissolving forms the medicine of 25% concentration (mass percent)
Liquid after adjusting pH to 9.5 with the sodium hydrate aqueous solution of 1mol/L, adds in a concentration of 30% peroxide of 1.0% medicine liquid volume
Change hydrogen, after persistently stirring 20 hours, pH to 7.0 adjusted with the aqueous hydrochloric acid solution of 1mol/L, backward liquid in be gradually added 3.0
The sodium chloride of (mass ratio) is measured again, is stirred to the methanol (mass volume ratio) for being completely dissolved 20 times of amounts of addition in backward liquid, it is heavy
It forms sediment, filters to obtain Enoxaparin Sodium centre product；Enoxaparin Sodium finished product is obtained by this step repetitive operation is primary.By Enoxaparin Sodium into
Product are added in purified water, and stirring and dissolving forms the liquid of 45% concentration (mass percent), liquid through 0.1 μm of membrane filtration,
It is spray-dried to obtain Enoxaparin Sodium highly finished product.
Gained Enoxaparin Sodium is detected after the long term test of 12 months, as a result as follows：
Claims (4)
1. a kind of preparation method of Enoxaparin Sodium crude product, it is characterised in that comprise the steps of：
1) benzethonium chloride aqueous solution is slowly added in heparin sodium water solution, it will reaction after reaction being stirred at room temperature 2-4 hours
Liquid filters, purifying water washing, is dried in vacuo to obtain heparin quaternary ammonium salt；
2) heparin quaternary ammonium salt obtained by step 1) is dissolved in dichloromethane, adds in benzyl chloride, it is small that 21-25 is reacted at 30-40 DEG C
When after be down to room temperature, add in 10% sodium acetate methanol solution, standing sedimentation 3 hours after being stirred to react 20-40 minute, suction filtration, institute
It obtains filter cake and is dried in vacuo to obtain heparin benzyl ester salt at room temperature；
3) heparin benzyl ester salt obtained by step 2) is dissolved in water and is made into heparin benzyl ester salting liquid, be heated to 60-65 DEG C, then add in
The sodium hydroxide solution of the 0.2M of isometric 60-65 DEG C of heparin benzyl ester salting liquid is cooled to 0-5 DEG C after being stirred to react 1 hour, take out
It is 6.5-6.8 that reaction solution PH is adjusted after filter, and sodium chloride is added to be made into salting liquid, is filtered after being settled 3 hours with 2.5-4 times of methanol, is filtered
Cake is dried in vacuo to obtain Enoxaparin Sodium crude product at 40 DEG C.
A kind of 2. preparation method of Enoxaparin Sodium crude product as described in claim 1, which is characterized in that heparin sodium in step 1)
Aqueous solution is that the heparin sodium of 1 parts by weight is dissolved in the purified water of 12-14 parts by weight and is obtained, and benzethonium chloride aqueous solution is by 2.2-
The benzethonium chloride of 2.8 parts by weight is dissolved in the purified water of 4.5-5.5 parts by weight and obtains, and vacuum drying temperature is 45-55 DEG C.
3. a kind of preparation method of Enoxaparin Sodium crude product as described in claim 1, which is characterized in that be by 1 in step 2)
The heparin quaternary ammonium salt of parts by weight is dissolved in the dichloromethane of 9-13 times of parts by volume, and the dosage of benzyl chloride is heparin quaternary ammonium salt quality
2 times, the dosage of sodium acetate is 2 times of heparin quaternary ammonium salt quality.
A kind of 4. preparation method of Enoxaparin Sodium crude product as described in claim 1, which is characterized in that heparin benzyl in step 3)
Ester salting liquid is that the heparin benzyl ester salt of 1 parts by weight is dissolved in the water of 10-14 parts by weight, and sodium chloride dosage is heparin benzyl ester salt
1.5-3.0 again.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101165071A (en) * | 2006-10-20 | 2008-04-23 | 江苏江山制药有限公司 | Clexane and preparation method thereof |
| CN102603925A (en) * | 2012-03-21 | 2012-07-25 | 东营天东生化工业有限公司 | Method for directly producing enoxaparin sodium from crude product heparin sodium |
| CN102952202A (en) * | 2011-08-25 | 2013-03-06 | 苏州鸿洋医药科技有限公司 | Preparation method and use of ultralow-molecular weight heparin sodium |
| CN104558252A (en) * | 2015-02-03 | 2015-04-29 | 华北制药华坤河北生物技术有限公司 | Method for producing enoxaparin sodium by using crude sodium heparin products |
-
2016
- 2016-12-21 CN CN201611191786.5A patent/CN108219030A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101165071A (en) * | 2006-10-20 | 2008-04-23 | 江苏江山制药有限公司 | Clexane and preparation method thereof |
| CN102952202A (en) * | 2011-08-25 | 2013-03-06 | 苏州鸿洋医药科技有限公司 | Preparation method and use of ultralow-molecular weight heparin sodium |
| CN102603925A (en) * | 2012-03-21 | 2012-07-25 | 东营天东生化工业有限公司 | Method for directly producing enoxaparin sodium from crude product heparin sodium |
| CN104558252A (en) * | 2015-02-03 | 2015-04-29 | 华北制药华坤河北生物技术有限公司 | Method for producing enoxaparin sodium by using crude sodium heparin products |
Non-Patent Citations (1)
| Title |
|---|
| 于广利 等: "《糖药物学》", 31 October 2012, 中国海洋大学出版社 * |
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